PACE Trial and PACE Trial Protocol

And note that Simon's illustration uses a Normal distribution. It would be interesting to see that on a skewed distribution where the s.d. is disproportionately larger, and the mean is far off centre stage.

Kirsten Thomson
Hi, i've been emailing QM as a freedom for information request and have just found out that the long awaited "deterioration rates" from the PACE trial have just been accepted for publication in the Journal of Psychosomatic Research, after it was initially sent back for revisions. So we should get to read it soon! Although i wonder if "deterioration" will have been redefined like "recovered" was...

Four outcome categories were used to estimate the effect of each treatment on fatigue, anxiety, depression, and functional impairment. The Hospital Anxiety and Depression Scale was the most common measure of mood, while the Chalder Fatigue Scale and the SF-36 were the most commonly used measures of fatigue and functional impairment, respectively. A complete list of the measures used to represent each category is available from the corresponding author. Separate effect sizes were calculated for each relevant outcome measure. As a result, up to four effect sizes originated from each study. In the primary analysis, these effect sizes were aggregated (assuming dependence), so that each study contributed a single weighted ES to the overall estimate of effect. Effect sizes were calculated for post-treatment outcomes only, as sufficient follow-up data to calculate effect sizes were often omitted from reports.

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Interestingly, this is what James Coyne said about another study?

Finally, I challenged the authors’ including two separate effect sizes from the same study, violating the requirement for statistical independence.

Not PACE Trial related, and have not evaluated the details, but the conclusion about journals sounds familiar in general:

"Today is the 6 month anniversary of the publication of the original paper, and we are still no closer to discovering what’s actually going on behind the scenes at PLoS Biology. The take home lesson here is that if you find a problem with published science, you’re better off writing it down on paper and throwing it to sea in a bottle, than you are trying to engage in reasoned constructive conversation with the gatekeepers of information, the journals. It’s 2014 now, and this state of affairs just saddens me."

It is quite long so most people won't want to read it all. Anyway, she talks about the different levels she can be at (she's even able to go on five mile walks some times) and how they can vary a lot. Also, she describes how the same four severity levels she varies between can be described in two different ways.

I know this is getting to be quite a long post, but there’s another issue that I feel it’s important to address. That is the issue of subjective perception. Considering the scales used in the PACE trial are based on self-assessment questionnaires, I’m sure it would not be wrong to assume that an individual person’s mental state, based on anything from what kind of week they’ve had to how much they’re being told by an outside source that they should now be feeling better, would alter the results of that self-assessment. Let’s revisit those above average, average, below average and pretty dreadful weeks…

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[..]

People often talk about how emotional state can affect physical symptoms, but don’t tend to consider so much how physical symptoms can affect emotional state. If you asked me about my illness on a really great day, I can guarantee that you would get a positive and hopeful answer focused on the good stuff. If you asked me on my worst day, you would get crying and swearing and more crying, if you even got a response. On an average day, it would be more like “It is what it is, and I’m dealing with it. There are so many wonderful things in life that I can still experience and so many more awful things that I’m thankful for not having to go through”. How different do you think my self-assessment would be depending on what day you happened to ask my to fill in a questionnaire? And how different would it be if I was enrolled in a program of ‘treatment’ focused almost completely on my emotional state where I was constantly being told that the ‘treatment’ should be making me feel better?

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Choose two different days, weeks or months to ask me how I am and I will most likely give you two different answers. They will both be true.

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This last bit is relevant because, for example, recovery was measured at a single point in time.

Kirsten Thomson
Hi, i've been emailing QM as a freedom for information request and have just found out that the long awaited "deterioration rates" from the PACE trial have just been accepted for publication in the Journal of Psychosomatic Research, after it was initially sent back for revisions. So we should get to read it soon! Although i wonder if "deterioration" will have been redefined like "recovered" was...

The challenge in tracking health is to make sure that my reference point remains the same and that I'm not simply getting more used to life with ME/CFS. As I've written about before, I try to keep objective measures in place to make sure that doesn't happen. Even still, there were two recent reminders that, while I have improvement with treatment, I have also simply become more accustomed to being ill.

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It ends:

Now that same degree of SOB [Shortness of Breath] barely fazes me. Although the sensation of air starvation is equally severe, I simply go about my day as if everything were fine. It has become a part of life.

My conclusion is that while most of my perceived improvement over the last two years is real improvement, at least some small part of it must be attributable to me adapting to life with ME/CFS. I've tried very hard to keep my standards consistent for tracking purposes, but I don't think it's possible to ever keep them perfectly even over time.

The challenge in tracking health is to make sure that my reference point remains the same and that I'm not simply getting more used to life with ME/CFS. As I've written about before, I try to keep objective measures in place to make sure that doesn't happen. Even still, there were two recent reminders that, while I have improvement with treatment, I have also simply become more accustomed to being ill.

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It ends:

Now that same degree of SOB [Shortness of Breath] barely fazes me. Although the sensation of air starvation is equally severe, I simply go about my day as if everything were fine. It has become a part of life.

My conclusion is that while most of my perceived improvement over the last two years is real improvement, at least some small part of it must be attributable to me adapting to life with ME/CFS. I've tried very hard to keep my standards consistent for tracking purposes, but I don't think it's possible to ever keep them perfectly even over time.

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Very good points well made. There are two, connected symptoms that I became particularly accustomed to - anxiety and palpitations. The anxiety was almost ever-present, and the palpitations occurred mostly just after I lay down in bed. Once I realised that neither was related to any imminent threat, I stopped worrying about them and was able to ignore them to a significant extent.

Chronic fatigue syndrome (CFS) is characterised by chronic and severe fatigue leading to substantial impairments. According to the cognitive behavioural model of CFS behavioural and cognitive responses perpetuate CFS symptoms and disability. In secondary care treatment trials have shown that individual cognitive behaviour therapy (CBT) and graded exercise therapy (GET) aimed at these perpetuating factors leads to a significant reduction of fatigue and disabilities.In primary care chronic fatigue is more common and appears to respond to a variety of approaches. CBT, GET and counselling are all effective. These approaches will be described and mechanisms of change will be presented.

Where is the PACE mediators paper!? Are they holding it back in the hope that 2.5 year data will allow them to claim being in receipt of benefits/being a member of a patient group/etc harms recovery, after failing to get these results for the initial data?

The Oxford criteria include people with psychological illness and by lessening the entry criteria, the study was slanted towards people with very mild disease.

The “standard medical care” was not what most people would get from their GP.

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Slide 41. PACE: definitely not the last word (2)

Other weaknesses:
- intention to treat analysis poorly applied
- exaggerated claims made about regarding outcomes
-improvement marginal for all therapies
- many showed no improvement
- however, adverse consequences were rare.

It was a randomised-control trial so the intention was to do the outcome analysis on the original entry criteria, as is proper. However, people dropped out and the outcomes were decided on those who stayed which caused an overestimation of benefits from the treatments and “made a nonsense of their final analysis.”

A bit OT, but I was just reading a bit of an irritating response to PACE from when it was first published. Then googled the guy who wrote it, and found that RateMDs.com gave him entirely negative reviews for being paid by insurance companies to push patients through 'rehabilitation' they found harmful:

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1100 Burloak Drive, Suite 603, Burlington, Ontario L7L 6B2
Tel. 905.319.0202 • Fax 905.319.9055
E-mail: inquiries@odysseyhealthservices.comwww.odysseyhealthservices.com
Dr. Richard G. Marlin, Director
Treating Chronic Fatigue Syndrome: What Works? What Doesn’t?
What constitutes effective treatment for chronic fatigue syndrome (also referred to as
myalgic encephalomyelitis and chronic fatigue and immune dysfunction syndrome) has
been a matter of considerable debate and dispute.
Several systematic reviews of the literature in the last 10 years have concluded that
cognitive behavioural therapy and graded exercise have been the only treatments with
demonstrated efficacy to both improve function and decrease symptoms in patients
diagnosed with chronic fatigue syndrome1.
Most unfortunately, these treatments have not been well received by patient support
groups, and alternatives have been advocated in various publications in spite of the lack
of empirical evidence supporting these alternative recommendations.
As an example, a paper was published by Carruthers et al2
(referred to as ‘Canadian
Consensus Document’) presenting a variety of suggestions, described in the paper as the
clinical opinions of the authors, with regard to treatment. These suggestions did not
represent empirically supported treatments.One of the most significant points of contention and controversy between the

mainstream, empirically-supported literature and the opinions reflected in this document

had to do with whether increases in function and exercise should be progressed in a

carefully graduated fashion but independent of the patient’s experience of their

symptoms, or whether the patient’s level of activity needed to be actively modulated

based upon their experience of fatigue and other symptoms.
It is quite well established in the chronic pain literature that activities should be quota-
based rather than symptomatically-based.3
1 Whiting, P.; Bagnall, A.; Sowden, A., Cornell, J., Mulrow, C. and Ramirez, G.: Interventions for
the Treatment and Management of Chronic Fatigue Syndrome: a Systematic Review, Journal of
the American Medical Association, September 19, 2001, Volume 286, Number 11; Chambers, D.,
Bagnall, A., Hempel, S. and Forbes, C. (2006) Interventions for the Treatment, Management and
Rehabilitation of Patients with Chronic Fatigue Syndrome/Myalgic encephalomyelitis: an Updated
Systematic Review. Journal of the Royal Society of Medicine, 99, 506-520; Prins, J., van der
Meer, J. and Bleijen, G. (2006) Chronic Fatigue Syndrome. Lancet January 28, 2006.
Indeed it is well established that basing
activity upon the symptom of pain will reinforce fear and avoidance and result in
2 Carruthers, B.M., Jain, A.K., DeMeirleir, K.L. et al (2003) Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal
of Chronic Fatigue Syndrome, 11 7-97
3 See Flor and Turk in Melzack and Wall’s Textbook of Pain, 5th Edition, pp 241-258.Page 2

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diminished function and an increased experience of pain.
The authors of the Carruthers et al paper argued that pursuing such a strategy with
chronic fatigue syndrome, in their clinical experience, produced a significant number of
untoward adverse events and might indeed be harmful to patients. Once again the
authors acknowledge that such concerns and predictions were based upon their clinical
experience and not upon well-controlled published studies.
Fortunately, White, Goldsmith, Johnson et al recently completed a multicentre
comparison of Cognitive Behaviour Therapy, Graded Exercise Therapy, Specialist
Medical Care, and what they characterize as Adaptive Pacing Therapy (designed to
formally implement the kinds of recommendations outlined in the Carruthers et al paper).
The White et al paper was very recently published on-line (February 18th, 2011) in the
prestigious British medical journal Lancet.
White et al reported on the outcome of 641 patients, 160 of whom were assigned to the
Adaptive Pacing Therapy, 161 to the Cognitive Behaviour Therapy, 160 to the Graded
Exercise Therapy and 160 to the Specialist Medical Care group.
When the 3 active therapies were compared to Specialist Medical Care alone, both
Cognitive Behaviour Therapy and Graded Exercise Therapy produced an improvement in
self-reported fatigue scores, 52 weeks after starting treatment, as well as improvement in
self-reported functioning. No such difference was noted between Adaptive Pacing
Therapy and Specialist Medical Care alone.
When Cognitive Behaviour Therapy and Graduated Exercise Therapy were compared
directly to Adaptive Pacing Therapy, patients receiving Cognitive Behaviour Therapy and
Graded Exercise Therapy again reported less fatigue and better physical functioning
overall.
Furthermore, there were no significant differences in the frequency of serious adverse
reactions between many of the groups, with 2 adverse reactions reported in the Adaptive
Pacing Therapy Group, 3 adverse reactions in the Cognitive Behaviour Therapy, 2
adverse reactions in the Graded Exercise Therapy group and 2 adverse reactions in the
Specialist Medical Care alone group.
Review of the demographic data showed that patients averaged 38 years of age, were
77% female, and had an average duration of illness of 32 months (range 16 to 68
months). None of these demographic variables differed between groups of patients.
Patients were randomly assigned to treatment.
It is of interest to note that when patients were asked about their confidence about
treatment (prior to commencing treatment) only 57% of patients in the Cognitive
Behaviour Therapy reported being confident compared to 72% of patients in the Adaptive
Pacing Therapy group and 70% in the Graded Exercise Therapy group. For Specialist
Medical Care alone, only 41% of patient reported feeling confident.Page 3

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However, after treatment, 82% of patients in the Cognitive Behaviour Therapy group
reported they were satisfied with treatment compared to 88% in the Graded Exercise
Therapy group and 84% in the Adaptive Pacing Therapy group. A much lower level of
satisfaction (50%) was reported in the Specialist Medical Care alone.
Thus, when put to a multicentre, randomly assigned, carefully controlled empirical test,
Cognitive Behavioural Therapy and Graded Exercise Therapy were both demonstrated to
be superior to Adaptive Pacing Therapy, similar to the advice recommended in
Carruthers et al, as well as the advice recommended by Bested, Logan and Howe4 for
the treatment of chronic fatigue syndrome as well as fibromyalgia.An accompanying editorial5 noted that while the White et al study clearly demonstrated

Therapy demonstrated that patients could recover from chronic fatigue syndrome, further

study was required to isolate the effective elements of therapy and to further understand

why the Adaptive Pacing Therapy was ineffective.
Odyssey Health Services has treated many patients with chronic fatigue syndrome as
well as patients with fibromyalgia and other chronic pain syndromes. Our therapy has
always been individualized, modeled after the empirically supported therapies but
customized to individual patients and implemented with patients in the field.
Our therapy is combined aspects of cognitive behavioural therapy with graded exercise
therapy and insured concomitant treatment of other physical and mental health
difficulties. I published a study with my colleagues in the American Journal of Medicine6
demonstrating the effectiveness of this particular methodology with chronic fatigue
patients.
Unfortunately, as Simon Wessely7 speculated in a commentary accompanying the
systematic review of the evidence-based treatment for chronic fatigue syndrome reported
by Whiting et al in the Journal of the American Medical Association, the empirical
evidence does not always persuade patient support groups and others with strongly
entrenched beliefs about the nature of the illness and appropriate treatment.
Thus it can be expected that this recent study will generate considerable debate and
criticism. Nonetheless, the study adds significantly to the weight of evidence supporting
4 Bested, A., Logan, A. and Howe, R. (2006) Hope and Help for Chronic Fatigue Syndrome and
Fibromyalgia. Cumberland House (a handbook not subject to peer review as in a major journal)
5 Bleijenberg, G. and Knoop, H. (2011) Chronic Fatigue Syndrome: Where to PACE from here?
Lancet. Published on-line February 18, 2011.
6 Marlin, Anchel, Gibson, Goldberg and Swinton. (1998). An Evaluation of Multidisciplinary
Intervention for Chronic Fatigue Syndrome with Long-Term Follow-Up, and a Comparison with
Untreated Controls. American Journal of Medicine, 105 (3A), 1105-1145.
7 Wessely, S. (2001) Chronic Fatigue Syndrome – Trials and Tribulations. Journal of the American
Medical Association. 286, 11, 1378-1379.Page 4

* 23/02/14 1 1 1 1 Query: Should you contact your employer or union if you get a letter from your insurance carrier that you are going to be assessed at Odyssey Health Services where Dr. Marlin works out of? Respond

* 17/12/13 1 1 1 1 The College of Psychologists of Ontario for Dr. Richard Marlin are, https://members.cpo.on.ca/public_register/show/... & https://members.cpo.on.ca/public_register/print.... My LTD insurance provider, Great West Life, has a 'corporate contract' with Odyssey Health Services which is owned/operated by Dr. Richard Marlin. Unfortunately, I wasn't aware of Dr. Marlin's illegal&immoral activities until my involvement in the 'highly customized' program became so detrimental to my health that I was forced to hire a lawyer to remove me from his care & ensure my GWL salary replacement benefit wouldn't be impacted. I'm trying to recoup my financial loss in light of his admissions of professional misconduct. Unfortunately, patients/clients are responsible for researching medical providers, even when forced into treatment. I wish I was able to research his total disregard for the profession, illegal actions and admission of guilt before accepting imposed treatment. KNOW your rights! Respond

04/12/13 SYSTEM: 2 negative duplicate or disallowed ratings automatically removed
16/11/13 1 1 1 1 IT IS ORDERED THAT: Dr. Richard Marlin shall appear before the Discipline Committee to be reprimanded, and both the fact of the finding of misconduct and the fact of reprimand shall be published on the College’s Registrar and in the Bulletin. Read it all at this link: https://members.cpo.on.ca/members_search/print/1012 Shame on these types of companies and so called professionals. I advise everyone to make a complaint to the College of Psychologists who has had to deal with unprofessional conduct from Marlin and his staff. Caused me so much stress, pain and added sickness. No real therapy or help from any of the staff and the level of unprofessionalism was astonishing !!!! Respond 03/11/13 1 1 1 1 I was sent to Odyssey Health in Vancouver to be assessed by my LTD insurance company, RBC. Dr Marlin was seen only a couple times during the assessment and provided a great sales pitch of Odyssey Health. Remember they are being paid by your insurance company to assess your current status of health and whether you are capable of returning to work. If you aren't they will also try to do treatment and I am sure you will be miraculously healed by their treating psycologist/kinesiologist and back to work in no time...LOL. But according to my Doctor and lawyer this is a conflict of interest and they should not be doing treatment. They send very carefully worded letters to your Doctor looking for a signature of approval of treatment. I refused treatment as it is my medical right to choose who treats me. I cant state this more highly, USE A LAWYER AND KNOW YOUR RIGHTS, TALK WITH YOUR DOCTOR AND EXPLAIN WHO ODYSSEY IS. They will take advantage of you if you don't know your rights!! Respond
01/06/13 1 2 1 1 GWL sent me to Dr.Marlin for an assessment, they had me sign a bunch of papers letting my doctors give my medical records, I did this two days ago only to find this page and also found out that he has a pending investigation of medical misconduct. Link below. We do not know what to do, the insurance says we have to go there, but in our contract it says they can send you elsewhere. We are not looking for a lawyer because Odyssey wants to do these tests that take hours and I am unable to sit for more then a few minutes. I have to be lying down all the time. How am I going to do these tests. if anyone knows any good lawyers that has dealt with this company please let us know on a message here. I have been approved for CPP disability a year ago, I'm on two insurance LTD, one i'm approved past the 2 year mark and the other well here we are. if the gov. approves me, then why not GWL. it's ridiculous. Here's the link: https://members.cpo.on.ca/members_search/print/1012See Responses
08/01/13 1 4 1 1 This person Richard Marlin is clueless and makes me go through very painful exercises that puts me in bad relapses and my condition with fibromyalgia has gotten a lot worse and I'm so stressed out about his bullying techniques. Is he a doctor or what???? I'm in so much pain and so afraid of going back and I have no choice because Great West Life is forcing me. I can't sleep any-more I'm so stressed out. He's destroying me. Respond 22/04/11 1 1 1 2 I would find someone else to assist me with therapy Respond 06/04/11 1 5 1 1 The person above said it all. Right on the money. They treat medical issues with no medical doctors on staff and only treat with bullying tactics and painful exercises. Avoid at all costs!!! Respond 28/01/11 2 5 1 1 Richard Marlin works for insurance companies like Great West Life, in the interest of insurance companies and not in the interest of the patient being assessed and/or treated, if you want to call what they do treatment. All it does is make things terribly worse and they force you into pain inducing activities that you cannot do. Money racket and should not be allowed to practice as a Doctor. I was not allowed to give my opinions and made to seem like I didn't know what I was talking about when its my body and my medical issues over 2 decades. I finally had major surgery and the insurance hired these clowns to use their scamming techniques in an attempt to drive me off benefits. What a scam. Not recommended. If you can avoid Dr Richard Marlin and his Oddysey health services scam do so at all costs. It's an insurance ploy to scam beneficiaries out their disability benefits. Respectfully and honestly from Anonymous due to ongoing legal issues.

Mr Matthees sent a follow up message to Queen Mary, University of London (18 June 2014) "Reasons why the public interest strongly favours disclosure of the requested data: (FOI 2014/F73) 18th June 2014 Assertions about complete recover..."

Mr Matthees sent a follow up message to Queen Mary, University of London (18 June 2014) "Reasons why the public interest strongly favours disclosure of the requested data: (FOI 2014/F73) 18th June 2014 Assertions about complete recover..."

SF-36 data on healthy working age adults is not a Gaussian distribution. It looks more like a truncated exponential, from 0 to 100. The median is probably 100, although it would not surprise me in some cases if it were 95.

SD is, so far as I am aware, undefined for such functions. Its use in such cases has not been mathematically validated. Would any mathematicians care to comment?

Using SD on normal populations of healthy working age adults is therefore undefined, invalid or irrelevant. Hence no calculation can be made based on SD to define normal or recovered. Other criteria must be used.

So the entire recovery bluk paper is based on nonsense statistics. Hence its invalid. Its the same for any claims of return to normal. Normal is mathematically unsubstantiated in PACE.

Does this about sum it up? Are there additional issues? Is SD somehow valid for exponential and other functions and I am not aware of it?

This is quite separate from effect sizes, changing start and other endpoint criteria etc. after the trial was under way.

Any statistician should have warned them. The Lancet's statistician should have warned them. While I think they do cite multiple statisticians in these studies, were they even told the data is non-Gaussian? What proper statistical advice obtained? I can only conclude that either they did NOT get proper statistical advice (possibly because the statisticians were not properly briefed), or that the advice they got was incompetent.

SF-36 data on healthy working age adults is not a Gaussian distribution. It looks more like a truncated exponential, from 0 to 100. The median is probably 100, although it would not surprise me in some cases if it were 95.

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The median for the working age population (<65) is 100 and goes down to 95 for the full population. The 25th quartile is 80 for the entire population. 90 for the working population and 95 for the working population with no long term health problems.

SD is, so far as I am aware, undefined for such functions. Its use in such cases has not been mathematically validated. Would any mathematicians care to comment?
Using SD on normal populations of healthy working age adults is therefore undefined, invalid or irrelevant. Hence no calculation can be made based on SD to define normal or recovered. Other criteria must be used.

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For the exponential distribution the mean = SD but I don't know how they should therefore be calculated when they differ to get an accurate estimate. But the distribution is not that good a fit to the exponential. Hence better to use median and percentiles which are more robust to noise.
The other question is for recovery what set of people do you compare to. Those who are healthy or healthy + long term health problems.
There are other problems using the mean and standard deviation given what is probably a non-linear scale. i.e. is the difference between not being able to wash and dress and having difficulty with washing and dressing the same as the difference between having difficulty with vigorous exercise and having no difficulty.

Any statistician should have warned them. The Lancet's statistician should have warned them. While I think they do cite multiple statisticians in these studies, were they even told the data is non-Gaussian? What proper statistical advice obtained? I can only conclude that either they did NOT get proper statistical advice (possibly because the statisticians were not properly briefed), or that the advice they got was incompetent.

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A statistician should know the assumptions for each test and check them! Really they should be treated as formal preconditions. One of the problems is that questionnaires are allowed to be called scales and then treated as such and after that abstraction is made no one thinks.

It is only valid to use the mean and standard deviation to calculate things when you know what the distribution is, and exactly what the calculation should give. For example, we know that mean ± s.d. for Normal/Gaussian distributions enclosed the middle two-thirds of the sample. If you don't know what the distribution is, and even more so if it is clear that it is very much not Gaussian, such calculations are meaningless simply because we have no idea what they would represent. Doing the same calculation on incomes in the UK in 2007/08 gives the result that earning minus £1.30 per hour is "within normal range".(evaluatingpace.phoenixrising.me/aps2furtherdetai.html)